Structural basis of Ca 2+-dependent activation and lipid transport by a TMEM16 scramblase

Elife. 2019 Jan 16;8:e43229. doi: 10.7554/eLife.43229.

Abstract

The lipid distribution of plasma membranes of eukaryotic cells is asymmetric and phospholipid scramblases disrupt this asymmetry by mediating the rapid, nonselective transport of lipids down their concentration gradients. As a result, phosphatidylserine is exposed to the outer leaflet of membrane, an important step in extracellular signaling networks controlling processes such as apoptosis, blood coagulation, membrane fusion and repair. Several TMEM16 family members have been identified as Ca2+-activated scramblases, but the mechanisms underlying their Ca2+-dependent gating and their effects on the surrounding lipid bilayer remain poorly understood. Here, we describe three high-resolution cryo-electron microscopy structures of a fungal scramblase from Aspergillus fumigatus, afTMEM16, reconstituted in lipid nanodiscs. These structures reveal that Ca2+-dependent activation of the scramblase entails global rearrangement of the transmembrane and cytosolic domains. These structures, together with functional experiments, suggest that activation of the protein thins the membrane near the transport pathway to facilitate rapid transbilayer lipid movement.

Keywords: S. cerevisiae; Scrambling; membrane channels; membrane structure; molecular biophysics; phospholipids; structural biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Aspergillus fumigatus / drug effects
  • Aspergillus fumigatus / metabolism*
  • Binding Sites
  • Biological Transport / drug effects
  • Calcium / pharmacology*
  • Ceramides / pharmacology
  • Fungal Proteins / chemistry
  • Fungal Proteins / metabolism*
  • Ligands
  • Lipids / chemistry*
  • Membrane Lipids / metabolism
  • Models, Molecular
  • Nanoparticles / chemistry
  • Phospholipid Transfer Proteins / chemistry
  • Phospholipid Transfer Proteins / metabolism*
  • Protein Conformation

Substances

  • Ceramides
  • Fungal Proteins
  • Ligands
  • Lipids
  • Membrane Lipids
  • Phospholipid Transfer Proteins
  • Calcium